Decreased birth weight, especially if due to intrauterine growth retardation, is associated with increased risk for cardiovascular disease and increased prevalence of insulin resistance, Type 2 diabetes mellitus, and hypertension. It has been proposed that fetal undernutrition may result in 'programming' of the fetus and thereby increase the risk for selected diseases later in life. The specific exposures, including any potential role of maternal nutrition, have not been determined. To date, no study with adequate bias control has showed that altered maternal nutrition in pregnancy can induce fetal programming. More specifically, any critical time periods in pregnancy during which maternal undernutrition could induce fetal programming have not been well established. It is therefore possible that the reported associations that are seen between size at birth and adult chronic disease risk may reflect confounding by a non-nutritional exposure, by social class, or by other factors. We propose to address these issues in a study of maternal undernutrition in identified trimesters of pregnancy and the subsequent risk of insulin resistance, Type 2 diabetes mellitus, hypertension, obesity and other risk factors for coronary artery disease in adulthood. We will examine whether (1) fetal programming can be induced by maternal undernutrition in pregnancy, (2) programming is limited to specific stages of gestation and (3) any effects are consistent across the examined cardiovascular disease risk factors. We will also evaluate the sensitivity and specificity of selected morphological measures of the hand as markers of the timing of intrauterine exposure. This study is feasible in the unique setting of the Netherlands, where selected men and women who were exposed prenatally to the Dutch famine of 1944-45 and who are now 55-60 years old can be identified, traced, and examined. We will study about 400 probands with prenatal famine exposure at pre-specified stages of pregnancy, 200 probands without prenatal famine exposure, and an unexposed same-sex sibling serving as a control for each proband. The total study size will be about 1,200 individuals. The unique circumstances of the famine and the novel use of a sib-paired design provide a well controlled assessment of the effect of maternal undernutrition at specific stages in pregnancy on her infant's disease risk later in life. We will establish the degree to which reported associations between birth weight and cardiovascular disease risk could reflect a shared maternal nutritional exposure. Answers to these unresolved issues are essential for further targeted studies into the mechanism of fetal programming in humans.